Alzheimer's Disease (AD) is a progressive neurodegenerative condition affecting a substantial proportion of people over the age of 65. There is presently no known cure. One hallmark of AD neuropathology includes neurofibrillary tangles involving neuronal processes and closely associated with gliotic astrocytes and with macrophages. Another hallmark of AD is the presence in the brain of affected individuals of "plaques" composed of a variety of proteins, glycoproteins, and other components. These plaques always contain a high proportion of .beta.-amyloid peptide, a 42-43 amino acid peptide aberrantly cleaved from the amyloid precursor protein.
Though normally observed in blood and cerebrospinal fluid, .beta.-amyloid peptide in an aggregated form is considered partly responsible for the noted neuronal death observed in AD (Koh, et al., Brain Res. 533:315 (1990); Mattson, et al., J. Neurosoi, 12:376 1992, etc.). Exposure of brain cells cultured in vitro to .beta.-amyloid peptide results in the degeneration of these cells. How this aggregated peptide mediates neuronal death is unclear, yet published reports suggest a programmed cell death or apoptotic mechanism. Loo, et al., PNAS, 90:7951 (1993).
Neuronal death found in AD involves the loss of specific neuronal subtypes, possibly by the aforementioned mechanism of programmed cell death/apoptosis (PCD), an active suicide program that differs markedly from necrotic death (Loo, et al., PNAS 90:7951, 1993). The mechanism of programmed cell death induction in neurons is unclear, yet measurable/observable characteristics of PCD exist. Examples of changes observed during the process of PCD are chromatin condensation or margination, synthesis of required death proteins, DNA fragmentation into repeating 200 bp units. Increases in certain transcription and translation products that precede the programmed death are also observed.
Other amyloidogenic diseases exist that are associated with .beta.-amyloid. These include Downs Syndrome and Hereditary Cerebral Hemorrhage with Amyloidosis-Dutch Type (HCHWA-D).
Alkaline phosphatases are a family of enzymes which serve diverse functions in mammalian cells. The major activity of these enzymes is to remove phosphate from nucleotides, and the 5' nucleotidases are included in this family. While specific chemical reactions catalyzed by these enzymes are well characterized, their role in cellular metabolism and regulation is less clearly defined.
Levamisole is an alkaline phosphatase inhibitor sold commercially under the brand name "Ergamisol" by Janssen Pharmaceutica of Piscataway, N.J. This product is available in tablets of levamisole hydrochloride for oral administration that contain the equivalent of 50 mg of levamisole base. Levamisole has been used in the treatment of colon cancer. Recommended dosage for treatment of colon cancer is 50 mg every eight hours for three days.
Acid phosphatases are another family of enzymes that serve diverse functions in mammalian cells.
European patent Application No. 91107844.2, Publication No. 0457295A2, purports to disclose the use of protein phosphatase inhibitors, such as okadaic acid, calyculin-A and vanadate for the treatment of amyloidosis associated with AD.